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Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages

Soo-Ho Choi1, Huiyong Yin2, Amir Ravandi3

  • 1Department of Medicine, University of California San Diego, La Jolla, California, United States of America.

Plos One
|December 31, 2013
PubMed

Insights

Researchers identified a specific oxidized cholesterol ester, BEP-CE, that activates macrophages via the TLR4/SYK pathway. This molecule, found in human plasma and atherosclerotic plaques, contributes to inflammation in atherosclerosis.

Area of Science:

  • Biochemistry
  • Immunology
  • Cardiovascular Research

Background:

  • Oxidation of low-density lipoprotein (LDL) is a key factor in atherosclerosis development.
  • Minimally oxidized LDL (mmLDL) triggers inflammatory responses, macropinocytosis, and lipid accumulation in macrophages.
  • Oxidized cholesterol esters (OxCEs) within mmLDL are biologically active components.

Purpose of the Study:

  • To identify the specific OxCE responsible for mmLDL's biological activity.
  • To characterize the signaling pathways activated in macrophages by this specific OxCE.
  • To investigate the role of this OxCE in the pathogenesis of atherosclerosis.

Main Methods:

  • Liquid chromatography-tandem mass spectrometry (LC-MS/MS) for molecular identification.
  • Biological assays using macrophages to assess cellular responses.
  • Experiments with knockout mice (TLR4 and SYK deficient) to confirm pathway involvement.
  • Analysis of human plasma and atherosclerotic plaque samples.

Main Results:

  • An oxidized cholesteryl arachidonate with bicyclic endoperoxide and hydroperoxide groups (BEP-CE) was identified as the active OxCE.
  • BEP-CE activates macrophages through TLR4/MD-2 binding, leading to TLR4 dimerization and SYK, ERK1/2, JNK, and c-Jun phosphorylation.
  • BEP-CE enhances macropinocytosis, promoting LDL uptake and foam cell formation, a process dependent on TLR4 and SYK.
  • BEP-CE was detected in human plasma and atherosclerotic lesions.

Conclusions:

  • BEP-CE is an endogenous ligand that activates the TLR4/SYK signaling pathway in macrophages.
  • BEP-CE-induced macrophage activation contributes to chronic inflammation in human atherosclerosis.
  • Targeting the BEP-CE/TLR4/SYK axis may offer therapeutic strategies for atherosclerosis.

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